rs780625433
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000275.3(OCA2):c.131delG(p.Gly44GlufsTer58) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,328 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000275.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
OCA2 | ENST00000354638.8 | c.131delG | p.Gly44GlufsTer58 | frameshift_variant | Exon 2 of 24 | 1 | NM_000275.3 | ENSP00000346659.3 | ||
OCA2 | ENST00000353809.9 | c.131delG | p.Gly44GlufsTer58 | frameshift_variant | Exon 2 of 23 | 1 | ENSP00000261276.8 | |||
OCA2 | ENST00000431101.1 | c.131delG | p.Gly44GlufsTer58 | frameshift_variant | Exon 2 of 7 | 3 | ENSP00000415431.1 | |||
OCA2 | ENST00000445578.5 | c.131delG | p.Gly44GlufsTer58 | frameshift_variant | Exon 2 of 6 | 3 | ENSP00000414425.1 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152160Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000204 AC: 5AN: 245200Hom.: 0 AF XY: 0.0000224 AC XY: 3AN XY: 133634
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461168Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726894
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152160Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5AN XY: 74330
ClinVar
Submissions by phenotype
Tyrosinase-positive oculocutaneous albinism Pathogenic:2
This OCA2 variant (rs780625433) is rare (<0.1%) in a large population dataset (gnomAD: 6/276568 total alleles; 0.002%; no homozygotes) and has been reported in ClinVar. This frameshift variant (p.Gly44fs) in exon 2 of 24 results in a premature termination signal likely leading to nonsense-mediated decay and lack of protein production. Bioinformatic analysis predicts the co-occurrence of this variant on the same haplotype as c.1103C>T, although this has not been confirmed experimentally to our knowledge. We consider c.131del to be pathogenic. -
The p.Gly44GlufsX58 variant in OCA2 has not been previously reported in individuals with disease but has been identified in 0.045% (4/8956) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 44 and leads to a premature termination codon 58 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Biallelic loss of function of the OCA2 gene is an established disease mechanism for oculocutaneous albinism type 2. In summary, although additional studies are required to fully establish its clinical significance, the p.Gly44GlufsX58 variant is likely pathogenic based upon predicted impact to the gene. -
SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:1
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Inborn genetic diseases Pathogenic:1
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Tyrosinase-positive oculocutaneous albinism;C1856895:SKIN/HAIR/EYE PIGMENTATION 1, BLUE/NONBLUE EYES Pathogenic:1
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not provided Pathogenic:1
This sequence change creates a premature translational stop signal (p.Gly44Glufs*58) in the OCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in OCA2 are known to be pathogenic (PMID: 19865097, 21541274). This variant is present in population databases (rs780625433, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with OCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 521067). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at